Skin Barrier Defects Research Articles

Extended Half-life Antibodies: A Narrative Review of a New Approach in the Management of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by intense pruritus and eczematous lesions, significantly impacting physical health and quality of life. The pathogenesis of AD involves genetic predisposition, immune dysregulation, and environmental factors, with a defective skin barrier playing a crucial role. Treatment options for AD include both topical and systemic therapies, with advanced treatments like Janus kinase inhibitors and biologics offering significant improvements but facing limitations in safety and dosing frequency. Extended half-life antibodies represent a promising advancement for the management of immune-mediated inflammatory diseases, including AD. These antibodies, engineered for prolonged circulation and reduced dosing frequency, target key cytokines and immune pathways known to be involved in the pathogenesis of AD, offering potential for less frequent administration while maintaining efficacy. Currently, two such agents are in phase2 trials. APG777, targeting interleukin-13 (IL-13), and IMG-007, targeting OX40 receptor, have shown promising preclinical and early clinical results. They demonstrated prolonged half-lives and the potential for less frequent dosage regimen, along with significant improvements in AD symptoms. These therapies could enhance patient adherence and reduce healthcare burdens by decreasing injection frequencies and clinic visits. As research continues, extended half-life antibodies could significantly improve AD management and patient quality of life. Further studies will determine the long-term safety and efficacy of extended half-life antibodies, with ongoing innovations in antibody engineering likely to broaden their applications and benefits.

Consensus Recommendations for the Management of Atopic Dermatitis in the United Arab Emirates.

Atopic dermatitis often begins in infancy and follows a chronic course of exacerbations and remissions. The etiology is complex and involves numerous factors that contribute to skin barrier defect and inflammation. In the Middle East, the burden of atopic dermatitis is understudied. Epidemiological data specific to the Gulf region are scarce but reveal a prevalence of up to about 40% in the United Arab Emirates. Region-specific factors, such as the climate and the frequency of consanguineous marriages, may affect atopic dermatitis incidence, prevalence, and evolution over time. A panel of experts predominantly from the United Arab Emirates analyzed the evidence from published guidelines, and considered expert guidance and local treatment practices to develop clear recommendations for the management of atopic dermatitis in the United Arab Emirates. They encourage a systematic approach for the diagnosis and treatment, using disease severity scores and quality-of-life measurement tools. Treatment recommendations take into consideration both established therapies and the approved systemic biologics dupilumab and tralokinumab, and the Janus kinase inhibitors baricitinib, upadacitinib, and abrocitinib.

Skin barrier, phenotypic and genotypic characterisation of autosomal recessive ichthyosis in TGM1-deficient Jack Russell Terriers and response to topical ceramide.

Autosomal recessive ichthyosis leads to structural or biochemical changes that impair skin barrier function. To assess (1) the phenotype and genotype in a litter of Jack Russell Terriers with autosomal recessive congenital ichthyosis (ARCI), and (2) the defective skin barrier and determine if a topical ceramide can modulate the barrier. A healthy dam and litter of Jack Russell Terrier puppies (healthy male, affected male and female), one affected adult Jack Russell Terrier and one unrelated healthy Jack Russell Terrier. A severe cornification defect was identified via examination of affected puppies. As the phenotype worsened, the affected puppies received a topical application of ω-0-acylceramide for 10 days. Before humane euthanasia, the skin barrier was evaluated via transepidermal water loss (TEWL), corneometry and pH in affected dogs. Genomic testing was performed, and skin samples were analysed by light and electron microscopy. Affected puppies were homozygous for the 1980 bp LINE-1 insertion in the TGM1 (transglutaminase 1) gene; the unaffected littermate and the dam were heterozygous carriers. ARCI puppies were underweight and had a severe hyperkeratotic phenotype that impaired mobility. TEWL was markedly higher in affected dogs. The cutaneous pH of affected puppies was higher than the normal littermate. Treatment of the skin with ω-0-acylceramide normalised the pH to match the littermate and decreased TEWL. Electron microscopy revealed marked attenuation of the cornified envelope. Dogs with TGM1-deficient ARCI have an impaired skin barrier. Topical therapy can partially repair the barrier defect.

The Role of Collagens in Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting both children and adults. The clinical picture of AD manifests in typical skin lesions, such as localized eczema and dry skin, with dominant, persistent itching that leads to sleep disturbances. The pathophysiology of AD has been extensively investigated with respect to epigenetic and genetic factors, skin barrier defects, as well as immunological and microbial disorders. However, to date, the involvement of extracellular matrix (ECM) elements has received limited attention. Collagen, a major component of the ECM, may serve as a therapeutic target for the future treatment of AD. This paper summarizes the role of collagens, which are the most abundant components of the extracellular matrix in AD.

Strategic Approaches in Formulation Development for Atopic Dermatitis

Atopic dermatitis (AD) is the most common chronic skin disease, significantly impacting patients’ quality of life. One of the most effective management approaches for AD involves addressing the defective skin barrier by urging AD patients to regularly use suitable moisturizers. Therapeutic moisturizers designed for AD are precisely formulated with ingredients targeting critical and often early symptoms of AD (e.g., itch, inflammation, damaged skin barrier). Dermo-cosmetic products, which are rich in moisturizing and emollient agents contributing to recovery as well as strengthening the skin barrier, have proven to be excellent adjuncts in AD treatment. There are various galenic forms of dermo-cosmetics, such as lotions, gels, creams, foams, and sprays, requiring a rationale in choosing ingredients for the product formulation and development. In addition, the role of moisturizer and emollient therapy to address skin dryness linked to dermatological conditions is hugely dependent on varying chemistry and morphology in the deeper regions of the skin. There are also limits to the efficacy of treatments, corticosteroid side effects, and product sensory appeal, which may decrease patient acceptance and compliance. The objective of this review is thus to offer a comprehensive overview of the critical aspects involved in the development of cosmetic vehicles, as well as a detailed examination of the primary ingredients used in formulations for AD.

The extracellular serine protease from Staphylococcus epidermidis elicits a type 2-biased immune response in atopic dermatitis patients.

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease with skin barrier defects and a misdirected type 2 immune response against harmless antigens. The skin microbiome in AD is characterized by a reduction in microbial diversity with a dominance of staphylococci, including Staphylococcus epidermidis (S. epidermidis). To assess whether S. epidermidis antigens play a role in AD, we screened for candidate allergens and studied the T cell and humoral immune response against the extracellular serine protease (Esp). To identify candidate allergens, we analyzed the binding of human serum IgG4, as a surrogate of IgE, to S. epidermidis extracellular proteins using 2-dimensional immunoblotting and mass spectrometry. We then measured serum IgE and IgG1 binding to recombinant Esp by ELISA in healthy and AD individuals. We also stimulated T cells from AD patients and control subjects with Esp and measured the secreted cytokines. Finally, we analyzed the proteolytic activity of Esp against IL-33 and determined the cleavage sites by mass spectrometry. We identified Esp as the dominant candidate allergen of S. epidermidis. Esp-specific IgE was present in human serum; AD patients had higher concentrations than controls. T cells reacting to Esp were detectable in both AD patients and healthy controls. The T cell response in healthy adults was characterized by IL-17, IL-22, IFN-γ, and IL-10, whereas the AD patients' T cells lacked IL-17 production and released only low amounts of IL-22, IFN-γ, and IL-10. In contrast, Th2 cytokine release was higher in T cells from AD patients than from healthy controls. Mature Esp cleaved and activated the alarmin IL-33. The extracellular serine protease Esp of S. epidermidis can activate IL-33. As an antigen, Esp elicits a type 2-biased antibody and T cell response in AD patients. This suggests that S. epidermidis can aggravate AD through the allergenic properties of Esp.

Breast Cancer–Related Lymphedema Results in Impaired Epidermal Differentiation and Tight Junction Dysfunction

Breast cancer-related lymphedema (BCRL) is characterized by skin changes, swelling, fibrosis, and recurrent skin infections. Clinical studies have suggested that lymphedema results in skin barrier defects; however, the underlying cellular mechanisms and the effects of bacterial contamination on skin barrier function remain unknown. In matched biopsies from patients with unilateral BCRL, we observed decreased expression of filaggrin and the tight junction protein zona occludens-1 (ZO-1) in skin affected by moderate lymphedema, or by subclinical lymphedema in which dermal backflow of lymph was identified by indocyanine green lymphography, relative to controls (areas without backflow and from the unaffected arm). In vitro stimulation of keratinocytes with lymph fluid obtained from patients undergoing lymphedema surgery led to the same changes, as well as increased expression of keratin 14, a marker of immature keratinocytes. Finally, using mouse models of lymphedema, we showed that like the clinical scenario, the expression of skin barrier proteins was decreased relative to normal skin and that colonization with S. epidermidis bacteria amplified this effect, as well as lymphedema severity. Taken together, our findings suggest that lymphatic fluid stasis contributes to skin barrier dysfunction in lymphedema.

Fungal Head and Neck Dermatitis: Current Understanding and Management.

Head and neck dermatitis (HND) is a form of atopic dermatitis (AD) that affects the seborrheic areas of the body and causes greater quality of life detriments than other types of AD. HND can be challenging to treat since first-line topical therapies may be ineffective or intolerable for long-term use on areas affected by HND while dupilumab may cause dupilumab-associated HND (DAHND). Current evidence implicates fungi, particularly Malassezia spp., in the pathogenesis of HND. Penetration of fungal antigens through the defective AD skin barrier activates the innate and adaptive immune systems to cause cutaneous inflammation via the T helper (Th)17 and/or Th2 axes. Malassezia sensitization may distinguish HND from other forms of AD. Multiple double-blind, placebo-controlled trials have shown antifungals to benefit HND, yet the persistence of symptom reliefwith sustained use remains unclear. Oral antifungals appear more effective than topical antifungals but may be harmful with long-term use. DAHND may also be fungal-mediated given improvement with antifungals and evidence of an overactive immune response against Malassezia in these patients. Janus kinase inhibitors are effective for HND, including DAHND, but may cause significant side effects when administered systemically. OX40/OX40L inhibitors and tralokinumab may be promising options for HND on the horizon. Demographic and environmental factors influence the host mycobiome and should be considered in future precision-medicine approaches as microbiome composition and diversity are linked to severity of HND.

Impaired skin barrier and allergic sensitization in 16-year-old adolescents

Abstract Background Transepidermal water loss (TEWL) has been used to measure skin barrier function and has been associated with atopic dermatitis and allergic diseases in infancy. However, few studies have assessed the association between TEWL and allergic diseases in adolescents. Objective To investigate the association between TEWL and allergic sensitizations in 16-year-old adolescents. Materials and methods The study was conducted in 78 adolescents of the PASTURE study. Different types of sensitization (seasonal, perennial, inhalant, food and any) were defined using serum specific immunoglobulin E (IgE) and skin prick test. TEWL was measured on the crook of either right or the left arm using a TEWAMETER® TM 300 (Courage + Khazaka electronic, Cologne, Germany) at mean temperature and humidity of 24.1 °C and 36.1%, respectively. The mean TEWL and interquartile range (IQR) were 11.9 ± 4.4 and 4.8 g/m2/h respectively. Results In our study, TEWL was positively associated with any sensitization (adjusted odds ratio [OR] per-IQR of the probability of increased TEWL [95% confidence interval]: OR 2.64; [1.12–6.19]; p = 0.03) and allergic rhinoconjunctivitis (ARC; OR 1.92; [1.04–3.54]; p = 0.04), but not with asthma or atopic dermatitis. When separating any sensitization into perennial and seasonal, only perennial sensitization (OR 3.30; [1.42–7.43]; p = 0.005) was associated with TEWL. Conclusion In the present study, we show the association of defective skin barrier function measured as TEWL with perennial sensitization and ARC suggesting its possible role in the pathogenesis of ARC through sensitization.

Altered skin microbiome, inflammation, and JAK/STAT signaling in Southeast Asian ichthyosis patients

BackgroundCongenital ichthyosis (CI) is a collective group of rare hereditary skin disorders. Patients present with epidermal scaling, fissuring, chronic inflammation, and increased susceptibility to infections. Recently, there is increased interest in the skin microbiome; therefore, we hypothesized that CI patients likely exhibit an abnormal profile of epidermal microbes because of their various underlying skin barrier defects. Among recruited individuals of Southeast Asian ethnicity, we performed skin meta-genomics (i.e., whole-exome sequencing to capture the entire multi-kingdom profile, including fungi, protists, archaea, bacteria, and viruses), comparing 36 CI patients (representing seven subtypes) with that of 15 CI age-and gender-matched controls who had no family history of CI.ResultsThis case–control study revealed 20 novel and 31 recurrent pathogenic variants. Microbiome meta-analysis showed distinct microbial populations, decreases in commensal microbiota, and higher colonization by pathogenic species associated with CI; these were correlated with increased production of inflammatory cytokines and Th17- and JAK/STAT-signaling pathways in peripheral blood mononuclear cells. In the wounds of CI patients, we identified specific changes in microbiota and alterations in inflammatory pathways, which are likely responsible for impaired wound healing.ConclusionsTogether, this research enhances our understanding of the microbiological, immunological, and molecular properties of CI and should provide critical information for improving therapeutic management of CI patients.

Skin barrier-inflammatory pathway is a driver of the psoriasis-atopic dermatitis transition.

As chronic inflammatory conditions driven by immune dysregulation are influenced by genetics and environment factors, psoriasis and atopic dermatitis (AD) have traditionally been considered to be distinct diseases characterized by different T cell responses. Psoriasis, associated with type 17 helper T (Th17)-mediated inflammation, presents as well-defined scaly plaques with minimal pruritus. AD, primarily linked to Th2-mediated inflammation, presents with poorly defined erythema, dry skin, and intense itching. However, psoriasis and AD may overlap or transition into one another spontaneously, independent of biological agent usage. Emerging evidence suggests that defects in skin barrier-related molecules interact with the polarization of T cells, which forms a skin barrier-inflammatory loop with them. This loop contributes to the chronicity of the primary disease or the transition between psoriasis and AD. This review aimed to elucidate the mechanisms underlying skin barrier defects in driving the overlap between psoriasis and AD. In this review, the importance of repairing the skin barrier was underscored, and the significance of tailoring biologic treatments based on individual immune status instead of solely adhering to the treatment guidelines for AD or psoriasis was emphasized.

Immunomodulatory and anti-angiogenesis effects of excavatolide B and its derivatives in alleviating atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin condition primarily driven by T helper 2 (Th2) cytokines, resulting in skin barrier defects, angiogenesis, and inflammatory responses. The marine natural product excavatolide B (EXCB), isolated from the Formosan Gorgonian coral Briareum stechei, exhibits anti-inflammatory and analgesic properties. To enhance solubility, EXCB is chemically modified into the derivatives EXCB-61 salt and EXCB-79. The study aims to investigate the therapeutic effects of these compounds on dinitrochlorbenzene (DNCB)-induced skin damage and to elucidate the underlying anti-inflammatory and anti-angiogenesis mechanism. In vitro, using lipopolysaccharide (LPS)-induced RAW 264.7 cells, all compounds at 10 μM significantly inhibited expression of inflammatory proteins (inducible nitric oxide synthase and cyclooxygenase-2), vascular endothelial growth factor (VEGF), and cytokines (interleukin (IL)−1β, IL-6, and IL-17A). In vivo, topical application of these compounds on DNCB-induced AD mice alleviated skin symptoms, reduced serum levels of IgE, IL-4, IL-13, IL-17, and interferon-γ, and moderated histological phenomena such as hyperplasia, inflammatory cell infiltration, and angiogenesis. The three compounds restored the expression of skin barrier-related proteins (loricrin, filaggrin, and claudin-1) and reduced the expression of angiogenesis-related proteins (VEGF and platelet endothelial cell adhesion molecule-CD31) in the tissues. This is the first study to indicate that EXCB, EXCB-61 salt, and EXCB-79 can treat AD disease by reducing inflammation and angiogenesis. Hence, they may be considered potential candidates for the development of new drugs for AD.

A highly soluble form of rutin for instant resolution of mask-wearing related disorders.

The COVID-19 pandemic brought about a new normal, necessitating the use of personal protective equipment (PPE) like face shields, surgical masks, gloves, and goggles. However, prolonged mask-wearing introduced skin-related issues due to changes in the skin's microenvironment, including increased humidity and temperature, as well as pressure on the skin. These factors led to skin deformation, vascular issues, edema, and inflammation, resulting in discomfort and cosmetic concerns. Clinical reports quickly highlighted the consequences of long-term mask use, including increased cases of "maskne" (mask-related acne) or mask-wearing related disorders such as rosacea flare-ups, skin-barrier defects, itching, erythema, redness, hyperpigmentation, and lichenification. Some of these issues, like inflammation, oxidative stress, and poor wound healing, could be directly linked to acne-related disorders or skin hypoxia. To address these problems, researchers turned to rutin, a well-known flavonoid with antioxidant, vasoactive, and anti-inflammatory properties. However, rutin's poor water solubility presented a challenge for cosmetic formulations. To overcome this limitation, a highly water-soluble form of rutin was developed, making it suitable for use at higher concentrations. In vitro and exvivo tests were conducted, as well as an innovative clinical trial including volunteers wearing surgical masks for at least 2 h, to evaluate the biological activity of this soluble rutin on the main skin concerns associated with mask-wearing (inflammation, oxidative stress, skin repair, hyperpigmentation, and skin redness). The invitro results showed that the active ingredient significantly reduced oxidative stress, improved wound healing, and reduced inflammation. In dark skin explants, the active ingredient significantly reduced melanin content, indicating its lightening activity. This effect was confirmed in the clinical study, where brown spots decreased significantly after 4 days of application. Moreover, measurements on volunteers demonstrated a decrease in skin redness and vascularization after the active ingredient application, indicating inflammation and erythema reduction. Volunteers reported improved skin comfort. In summary, the COVID-19 pandemic led to various skin issues associated with mask-wearing. A highly soluble form of rutin was developed, which effectively addressed these concerns by reducing inflammation, oxidative stress, and hyperpigmentation while promoting wound healing. This soluble rutin offers a promising solution for the rapid treatment of maskne-related disorders and other skin problems caused by prolonged mask use.

Phenotypes, endotypes and genotypes of atopic dermatitis and allergy in populations of African ancestry on the continent and diaspora.

Atopic dermatitis is a complex inflammatory condition characterized by synergist interactions between epidermal and immune related genotypes, skin barrier defects and immune dysregulation as well as microbial dysbiosis. Ethnicity-specific variations in clinical presentation, immune endotypes and genetic susceptibility have been described in diverse populations. We summarize available data with specific consideration of AD in populations of African ancestry. Some highlights include the observation of AD lesions on extensor surfaces, lichen planus-like AD, prurigo type AD and follicular AD in African populations. In addition, a consistent absence of dominant filaggrin gene defects has been reported. The detection of normal filaggrin protein content in AD skin implicates the contribution of alternative mechanisms in the pathogenesis of AD in African patients. Markedly high IgE has been described in paediatric and adult African AD. While Th2, Th22 and Th17 activation in African AD skin shares the same direction as with other populations, it has been noted that the magnitude of activation is dissimilar. Reduced Th17 cytokines have been observed in the circulation of moderate to severe paediatric AD.

Endothelial Protein C Receptor and 3K3A-Activated Protein C Protect Mice from Allergic Contact Dermatitis in a Contact Hypersensitivity Model.

Endothelial protein C receptor (EPCR) is a receptor for the natural anti-coagulant activated protein C (aPC). It mediates the anti-inflammatory and barrier-protective functions of aPC through the cleavage of protease-activated receptor (PAR)1/2. Allergic contact dermatitis is a common skin disease characterized by inflammation and defective skin barrier. This study investigated the effect of EPCR and 3K3A-aPC on allergic contact dermatitis using a contact hypersensitivity (CHS) model. CHS was induced using 1-Fluoro-2,4-dinitrobenzene in EPCR-deficient (KO) and matched wild-type mice and mice treated with 3K3A-aPC, a mutant form of aPC with diminished anti-coagulant activity. Changes in clinical and histological features, cytokines, and immune cells were examined. EPCRKO mice displayed more severe CHS, with increased immune cell infiltration in the skin and higher levels of inflammatory cytokines and IgE than wild-type mice. EPCR, aPC, and PAR1/2 were expressed by the skin epidermis, with EPCR presenting almost exclusively in the basal layer. EPCRKO increased the epidermal expression of aPC and PAR1, whereas in CHS, their expression was reduced compared to wild-type mice. 3K3A-aPC reduced CHS severity in wild-type and EPCRKO mice by suppressing immune cell infiltration/activation and inflammatory cytokines. In summary, EPCRKO exacerbated CHS, whereas 3K3A-aPC could reduce the severity of CHS in both EPCRKO and wild-type mice.

Comparison of skin barrier abnormalities and epidermal ceramide profiles among three ω-O-acylceramide synthesis-deficient mouse strains

BackgroundThe epidermis contains many structurally diverse ceramides, which form the skin permeability barrier (skin barrier). Mutations in genes involved in the synthesis of ω-O-acylceramides (acylceramides) and protein-bound ceramides cause ichthyosis. ObjectiveWe aimed to elucidate the relationship between the degree of skin barrier impairment and changes in epidermal ceramide profiles caused by mutations in acylceramide synthesis genes. MethodsKnockout (KO) mice of three genes—fatty acid (FA) ω-hydroxylase Cyp4f39 (human CYP4F22 ortholog), FA elongase Elovl1, and acyl-CoA synthetase Fatp4—were subjected to transepidermal water loss measurement, toluidine blue staining, and epidermal ceramide profiling via liquid chromatography coupled with tandem mass spectrometry. ResultsTransepidermal water loss was highest in Cyp4f39 KO mice, followed by Elovl1 KO and Fatp4 KO mice, and Cyp4f39 KO mice also showed the strongest degree of toluidine blue staining. In Cyp4f39 KO, Elovl1 KO, and Fatp4 KO mice, acylceramide levels were 0.6%, 1.6%, and 12%, respectively, of those in wild-type mice. Protein-bound ceramide levels were 0.2%, 30%, and 33%, respectively, of those in wild-type mice. We also observed a near-complete absence of ω-hydroxy ceramides in Cyp4f39 KO mice, reduced total ceramide levels and shortened FA moieties in Elovl1 KO mice, and increased hydroxylated ceramide levels and slightly shortened FA moieties in Fatp4 KO mice. ConclusionsThe degree of reduction in protein-bound ceramide levels is probably related to the severity of skin barrier defects in these three strains. However, reduced acylceramide levels and other changes in ceramide composition unique to each KO strain are also involved.

Characterization of skin barrier defects using infrared spectroscopy in patients with atopic dermatitis.

Atopic dermatitis (AD) is characterized by skin barrier defects that are often measured by biophysical tools that observe the functional properties of the stratum corneum (SC). To employ in vivo infrared spectroscopy alongside biophysical measurements to analyse changes in the chemical composition of the SC in relation to AD severity. We conducted an observational cross-sectional cohort study where attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy measurements were collected on the forearm alongside surface pH, capacitance, erythema and transepidermal water loss (TEWL), combined with tape stripping, in a cohort of 75 participants (55 patients with AD stratified by phenotypic severity and 20 healthy controls). Common FLG variant alleles were genotyped. Reduced hydration, elevated TEWL and redness were all associated with greater AD severity. Spectral analysis showed a reduction in 1465 cm-1 (full width half maximum) and 1340 cm-1 peak areas, indicative of less orthorhombic lipid ordering and reduced carboxylate functional groups, which correlated with clinical severity (lipid structure r = -0.59, carboxylate peak area r = -0.50). ATR-FTIR spectroscopy is a suitable tool for the characterization of structural skin barrier defects in AD and has potential as a clinical tool for directing individual treatment based on chemical structural deficiencies.

Formylpeptide receptor 1 contributes to epidermal barrier dysfunction-induced skin inflammation through NOD-like receptor C4-dependent keratinocyte activation.

Skin barrier dysfunction may both initiate and aggravate skin inflammation. However, the mechanisms involved in the inflammation process remain largely unknown. We sought to determine how skin barrier dysfunction enhances skin inflammation and molecular mechanisms. Skin barrier defect mice were established by tape stripping or topical use of acetone on wildtype mice, or filaggrin deficiency. RNA-Seq was employed to analyse the differentially expressed genes in mice with skin barrier defects. Primary human keratinocytes were transfected with formylpeptide receptor (FPR)1 or protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) small interfering RNA to examine the effects of these gene targets. The expressions of inflammasome NOD-like receptor (NLR)C4, epidermal barrier genes and inflammatory mediators were evaluated. Mechanical (tape stripping), chemical (acetone) or genetic (filaggrin deficiency) barrier disruption in mice amplified the expression of proinflammatory genes, with transcriptomic profiling revealing overexpression of formylpeptide receptor (Fpr1) in the epidermis. Treatment with the FPR1 agonist fMLP in keratinocytes upregulated the expression of the NLRC4 inflammasome and increased interleukin-1β secretion through modulation of ER stress via the PERK-eIF2α-C/EBP homologous protein pathway. The activation of the FPR1-NLRC4 axis was also observed in skin specimens from old healthy individuals with skin barrier defect or elderly mice. Conversely, topical administration with a FPR1 antagonist, or Nlrc4 silencing, led to the normalization of barrier dysfunction and alleviation of inflammatory skin responses in vivo. In summary, our findings show that the FPR1-NLRC4 inflammasome axis is activated upon skin barrier disruption and may explain exaggerated inflammatory responses that are observed in disease states characterized by epidermal dysfunction. Pharmacological inhibition of FPR1 or NLRC4 represents a potential therapeutic target.

Helicobacter pylori infection attenuates 2,4-dinitrochlorobenzene-induced atopic dermatitis-like skin lesions in C57/BL6 mice

BackgroundAlthough numerous studies have suggested a negative correlation between Helicobacter pylori (H. pylori) infection and allergies, there has been limited research on the relationship between H. pylori infections and atopic dermatitis (AD). The present study aimed to investigate the effects of H. pylori infection in an AD mouse model and identify potential mechanisms related to type 2 immunity, skin barrier defects, and pruritus.MethodsA model of AD-like symptoms was established with 2,4-dinitrochlorobenzene (DNCB) after infection of the gastric cavity with H. pylori. Analysis of the expression of key inflammatory cytokines and serum levels of immunoglobulin E (IgE) was based on enzyme-linked immunosorbent assay (ELISA). The expression of filaggrin (FLG) and loricrin (LOR) were analyzed by immunohistochemistry staining. The evaluation of STAT1, STAT3, phosphorylated STAT1 (phospho-STAT1), and phosphorylated STAT3 (phospho-STAT1) expression levels in skin lesions was performed using western blot.ResultsThe present study showed that the H. pylori-positive AD group (HP+AD+) exhibited milder skin lesions, including erythema, erosion, swelling, and scaling, than the H. pylori-negative AD group (HP−AD+). Additionally, HP+AD+ displayed lower levels of IgE in serum, and downregulated expression of interleukins 4 and 31 (IL-4 and IL-31) in serum. Furthermore, HP+AD+ demonstrated higher expression of filaggrin and loricrin than HP−AD+. Notably, H. pylori significantly reduced the amount of phosphorylated STAT1 and STAT3.ConclusionHelicobacter pylori infection negatively regulates the inflammatory response by affecting inflammatory factors in the immune response, and repairs the defective epidermal barrier function. In addition, H. pylori infection may reduce IL-31, thereby alleviating pruritus. These effects may be associated with the inhibition of JAK–STAT signaling activation.

117 Molecular signatures of skin barrier defect and inflammation in Netherton syndrome uncovered by comparing patients to viable Spink5 knock-out mice

117 Molecular signatures of skin barrier defect and inflammation in Netherton syndrome uncovered by comparing patients to viable Spink5 knock-out mice